Guo Chunguang, Liu Zaoqu, Yu Yin, Chen Yunfang, Liu Hui, Guo Yaming, Peng Zhenyu, Cai Gaopo, Hua Zhaohui, Han Xinwei, Li Zhen
Department of Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Front Genet. 2022 Mar 25;13:844800. doi: 10.3389/fgene.2022.844800. eCollection 2022.
Due to high invasiveness and heterogeneity, the morbidity and mortality of intrahepatic cholangiocarcinoma (ICC) remain unsatisfied. Recently, the exploration of genomic variants has decoded the underlying mechanisms of initiation and progression for multiple tumors, while has not been fully investigated in ICC. We comprehensively analyzed 899 clinical and somatic mutation data of ICC patients from three large-scale cohorts. Based on the mutation landscape, we identified the common high-frequency mutation genes (FMGs). Subsequently, the clinical features, prognosis, tumor mutation burden (TMB), and pharmacological landscape from patients with different mutation carriers were further analyzed. We found TP53 and KRAS were the common FMGs in the three cohorts. Kaplan-Meier survival curves and univariate and multivariate analysis displayed that TP53 and KRAS mutations were associated with poor prognosis. Considering the co-mutation phenomenon of TP53 and KRAS, we stratified patients into "Double-WT," "Single-Hit," and "Double-Hit" phenotypes by mutation status. Patients with the three phenotypes showed significant differences in the mutation landscape. Additionally, compared with "Double-WT" and "Single-Hit" phenotypes, patients with "Double-Hit" presented a dismal prognosis and significantly high TMB. Through chemotherapy sensitivity analysis, we identified a total of 30 sensitive drugs for ICC patients, of which 22 were drugs sensitive to "Double-WT," 7 were drugs sensitive to "Double-Hit," and only one was a drug sensitive to "Single-Hit." Our study defined a novel mutation classification based on the common FMGs, which may contribute to the individualized treatment and management of ICC patients.
由于肝内胆管癌（ICC）具有高度侵袭性和异质性，其发病率和死亡率仍不尽人意。最近，对基因组变异的探索已经解码了多种肿瘤发生和进展的潜在机制，但在ICC中尚未得到充分研究。我们全面分析了来自三个大规模队列的899例ICC患者的临床和体细胞突变数据。基于突变图谱，我们确定了常见的高频突变基因（FMGs）。随后，进一步分析了不同突变携带者患者的临床特征、预后、肿瘤突变负荷（TMB）和药理图谱。我们发现TP53和KRAS是三个队列中常见的FMGs。Kaplan-Meier生存曲线以及单因素和多因素分析显示，TP53和KRAS突变与预后不良相关。考虑到TP53和KRAS的共突变现象，我们根据突变状态将患者分为“双野生型”、“单突变型”和“双突变型”三种表型。三种表型的患者在突变图谱上存在显著差异。此外，与“双野生型”和“单突变型”表型相比，“双突变型”患者预后较差，TMB显著较高。通过化疗敏感性分析，我们确定了总共30种对ICC患者敏感的药物，其中22种对“双野生型”敏感，7种对“双突变型”敏感只有1种对“单突变型”敏感。我们的研究基于常见的FMGs定义了一种新的突变分类，这可能有助于ICC患者的个体化治疗和管理。
